What are the signs and symptoms of multiple myeloma relapse and how is it managed?

Signs and Symptoms of Multiple Myeloma Relapse and Management

Multiple myeloma relapse requires comprehensive evaluation with bone marrow biopsy, FISH studies, and imaging to identify both biochemical and clinical relapse features, followed by risk-stratified treatment with triplet therapy for most patients to reduce mortality and improve quality of life.

Signs and Symptoms of Relapse

Biochemical Relapse

• Rising serum or urine paraprotein levels without clinical symptoms 1
• Abnormal serum free light chain ratio
• Increasing clonal plasma cells in bone marrow

Clinical Relapse Signs

• CRAB features 1:
  • C: Hypercalcemia (>11 mg/dL)
  • R: Renal dysfunction (creatinine >2 mg/dL)
  • A: Anemia (hemoglobin <10 g/dL)
  • B: Bone lesions (new lytic lesions or fractures)
• Development of extramedullary plasmacytomas 1
• Circulating clonal plasma cells in peripheral blood 1
• High plasma cell S-phase fraction (>3%) 1

High-Risk Relapse Indicators

• Early relapse (<12 months from diagnosis) 1
• Relapse during maintenance therapy 1
• Relapse within 18 months post-ASCT 1
• Acquisition of high-risk cytogenetic abnormalities 1:
  • del(17p)
  • t(4;14)
  • t(14;16)
  • t(14;20)
  • 1q amplification
  • 1p deletion
  • MYC rearrangements

Evaluation of Relapse

Required Testing

1. Complete blood count to assess for anemia and other cytopenias
2. Chemistry panel for calcium, creatinine, and other markers
3. Serum and urine protein electrophoresis with immunofixation
4. Serum free light chain assay
5. Bone marrow biopsy with FISH studies to assess clonal plasma cells and cytogenetic risk 1
6. Advanced imaging 1:
   • PET/CT or PET/MRI (preferred for detecting active lesions)
   • Low-dose skeletal CT
   • MRI (especially for spinal assessment)
7. Flow cytometry to detect circulating plasma cells 1

Management Approach

Timing of Treatment

• Immediate treatment required for:
  • Clinical relapse with CRAB features 1
  • High-risk cytogenetics 1
  • Extramedullary disease 1
  • Early relapse post-transplant/initial therapy 1
  • Rapid rise in myeloma markers 1
• Observation appropriate for:
  • Slow, asymptomatic biochemical relapse in standard-risk patients 1
  • Close monitoring of symptoms, organ function, and paraprotein levels required 1

Treatment Selection

1. Triplet therapy is preferred for most patients at first relapse 1, 2

   • Combination of two novel agents plus steroid 1
   • Daratumumab-based combinations show superior outcomes 2

2. Preferred regimens based on prior therapy:

   • Daratumumab-lenalidomide-dexamethasone (DRd) - first choice for many patients 2
   • Daratumumab-pomalidomide-dexamethasone (DPd) - if lenalidomide-refractory 2
   • Carfilzomib-pomalidomide-dexamethasone (KPd) - alternative option 2
   • Ixazomib-lenalidomide-dexamethasone (IRd) - all-oral option for frail patients 2

3. Salvage ASCT consideration 2:

   • For fit patients with indolent relapse
   • Beneficial if first ASCT provided response lasting ≥18 months without maintenance or ≥36 months with maintenance
   • Shown to improve time to progression (19 months vs 11 months)

Risk-Adapted Approach

• High-risk patients (aggressive relapse, high-risk cytogenetics):

  • Continuous therapy recommended 1
  • Triple combination therapy preferred 1
  • Consider clinical trials when available 1

• Standard-risk patients (indolent relapse):

  • May benefit from periods without therapy between treatments 1
  • Treatment can be less intensive if patient has significant comorbidities 1

Management of Treatment-Related Toxicities

• Peripheral neuropathy 3:

  • Monitor for symptoms (burning sensation, hyperesthesia, hypoesthesia, paresthesia)
  • Dose reduction or less intense schedule if worsening occurs
  • Consider switching from bortezomib to carfilzomib if significant 2

• Hypotension 3:

  • Monitor throughout therapy, especially with bortezomib
  • Adjust antihypertensive medications, ensure hydration

• Cardiac toxicity 3:

  • Monitor for heart failure symptoms with proteasome inhibitors
  • Regular cardiac assessment for at-risk patients

• Thrombosis risk with immunomodulatory drugs 2:

  • Provide thromboprophylaxis (aspirin for average risk, anticoagulants for high-risk)

Common Pitfalls to Avoid

1. Failing to perform complete restaging at relapse 2
2. Not considering prior treatment response when selecting new therapy 2
3. Using single agents instead of combination therapy 2
4. Overlooking salvage transplant in eligible patients 2
5. Not adjusting therapy for frail patients 2
6. Delaying treatment in patients with high-risk features or clinical relapse 1

By following this risk-stratified approach to evaluation and management, patients with relapsed multiple myeloma can achieve optimal outcomes with improved survival and quality of life.